CN107753464A - It is encapsulated hollow silicon dioxide nano-particle, its preparation method and the application of bioactive ingredients - Google Patents
It is encapsulated hollow silicon dioxide nano-particle, its preparation method and the application of bioactive ingredients Download PDFInfo
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- CN107753464A CN107753464A CN201710718231.XA CN201710718231A CN107753464A CN 107753464 A CN107753464 A CN 107753464A CN 201710718231 A CN201710718231 A CN 201710718231A CN 107753464 A CN107753464 A CN 107753464A
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- silicon dioxide
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- nano particles
- bioactive ingredients
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- 125000001400 nonyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- LIXVMPBOGDCSRM-UHFFFAOYSA-N nonylbenzene Chemical compound CCCCCCCCCC1=CC=CC=C1 LIXVMPBOGDCSRM-UHFFFAOYSA-N 0.000 description 1
- 102000039446 nucleic acids Human genes 0.000 description 1
- 108020004707 nucleic acids Proteins 0.000 description 1
- 150000007523 nucleic acids Chemical class 0.000 description 1
- 125000002811 oleoyl group Chemical group O=C([*])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])/C([H])=C([H])\C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 210000000056 organ Anatomy 0.000 description 1
- 125000000913 palmityl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 201000002528 pancreatic cancer Diseases 0.000 description 1
- 208000008443 pancreatic carcinoma Diseases 0.000 description 1
- 229940049954 penicillin Drugs 0.000 description 1
- 125000002958 pentadecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 230000035699 permeability Effects 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 239000008363 phosphate buffer Substances 0.000 description 1
- 229920000724 poly(L-arginine) polymer Polymers 0.000 description 1
- 108010011110 polyarginine Proteins 0.000 description 1
- 229940068918 polyethylene glycol 400 Drugs 0.000 description 1
- 229920000656 polylysine Polymers 0.000 description 1
- 229920000642 polymer Polymers 0.000 description 1
- 239000005017 polysaccharide Substances 0.000 description 1
- 229920001282 polysaccharide Polymers 0.000 description 1
- 229920002223 polystyrene Polymers 0.000 description 1
- 239000011591 potassium Substances 0.000 description 1
- 229910052700 potassium Inorganic materials 0.000 description 1
- 239000001103 potassium chloride Substances 0.000 description 1
- 235000011164 potassium chloride Nutrition 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 238000009163 protein therapy Methods 0.000 description 1
- 239000012925 reference material Substances 0.000 description 1
- 230000003014 reinforcing effect Effects 0.000 description 1
- BOLDJAUMGUJJKM-LSDHHAIUSA-N renifolin D Natural products CC(=C)[C@@H]1Cc2c(O)c(O)ccc2[C@H]1CC(=O)c3ccc(O)cc3O BOLDJAUMGUJJKM-LSDHHAIUSA-N 0.000 description 1
- 230000008439 repair process Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 230000004044 response Effects 0.000 description 1
- 239000012266 salt solution Substances 0.000 description 1
- 238000001507 sample dispersion Methods 0.000 description 1
- 235000015170 shellfish Nutrition 0.000 description 1
- 229910052814 silicon oxide Inorganic materials 0.000 description 1
- 238000006884 silylation reaction Methods 0.000 description 1
- 239000011734 sodium Substances 0.000 description 1
- 229910052708 sodium Inorganic materials 0.000 description 1
- 239000011780 sodium chloride Substances 0.000 description 1
- 239000011775 sodium fluoride Substances 0.000 description 1
- 235000013024 sodium fluoride Nutrition 0.000 description 1
- DAEPDZWVDSPTHF-UHFFFAOYSA-M sodium pyruvate Chemical class [Na+].CC(=O)C([O-])=O DAEPDZWVDSPTHF-UHFFFAOYSA-M 0.000 description 1
- 229910052938 sodium sulfate Inorganic materials 0.000 description 1
- 235000011152 sodium sulphate Nutrition 0.000 description 1
- 238000003980 solgel method Methods 0.000 description 1
- 238000007614 solvation Methods 0.000 description 1
- UNFWWIHTNXNPBV-WXKVUWSESA-N spectinomycin Chemical compound O([C@@H]1[C@@H](NC)[C@@H](O)[C@H]([C@@H]([C@H]1O1)O)NC)[C@]2(O)[C@H]1O[C@H](C)CC2=O UNFWWIHTNXNPBV-WXKVUWSESA-N 0.000 description 1
- 210000000952 spleen Anatomy 0.000 description 1
- 125000004079 stearyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 230000004083 survival effect Effects 0.000 description 1
- 230000002194 synthesizing effect Effects 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 125000003396 thiol group Chemical class [H]S* 0.000 description 1
- 210000001519 tissue Anatomy 0.000 description 1
- 231100000419 toxicity Toxicity 0.000 description 1
- 230000001988 toxicity Effects 0.000 description 1
- 238000012549 training Methods 0.000 description 1
- YNJBWRMUSHSURL-UHFFFAOYSA-N trichloroacetic acid Chemical class OC(=O)C(Cl)(Cl)Cl YNJBWRMUSHSURL-UHFFFAOYSA-N 0.000 description 1
- 125000002889 tridecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
- QQQSFSZALRVCSZ-UHFFFAOYSA-N triethoxysilane Chemical compound CCO[SiH](OCC)OCC QQQSFSZALRVCSZ-UHFFFAOYSA-N 0.000 description 1
- 125000002948 undecyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])[H] 0.000 description 1
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Abstract
The present invention relates to hollow silicon dioxide nano-particle, its preparation method and the application for being encapsulated bioactive ingredients.The present invention relates to hollow silicon dioxide nano-particle, and it is the drug delivery system for loading bioactive ingredients.Specifically, the present invention relates to the Nano particles of silicon dioxide for being encapsulated in the bioactive ingredients in the housing with one or more comprising multi-layer silica dioxide housing, and its application in medicine delivery.
Description
The cross reference of related application
The application is related to and required the rights and interests for the U.S. Provisional Application 62/376,920 that August in 2016 is submitted on the 19th, institute
State U.S. Provisional Application content be integrally incorporated it is herein incorporated by reference.
Technical field
The present invention relates to hollow silicon dioxide nano-particle, and it is the drug delivery system for loading bioactive ingredients.Tool
Say, the present invention relates to the bioactive ingredients being encapsulated in comprising multi-layer silica dioxide housing with one or more in the housing body
Nano particles of silicon dioxide, and its application in medicine delivery.
Background technology
Produced and developed this as the development of the new form of therapy of therapeutic agent using giant molecule (such as protein or nucleic acid)
Kind giant molecule is delivered to the demand of the novel effective of its appropriate cell target.It has been found that nano-particle technology is applied to pharmacology
And medicine delivery.
The nano-carrier for macromolecular delivering, including polymer, liposome and inorganic nano-particle are had been developed for, such as
Nano particles of silicon dioxide.In various silica nano materials, hollow silicon dioxide nano-particle (HSN) is because of its uniqueness
Physical/chemical properties (such as macrovoid volume, chemical/thermal stability, high useful load, regulatable surface characteristic and excellent life
Thing compatibility) and it is considered to have the great potential as drug delivery system.Different from common solid mesoporosity titanium dioxide
Silicon nano (MSN), HSN can be encapsulated the material (such as bioactive ingredients) of large-size and because the unique form are (that is, porous
Shell and hollow inner space) and show higher useful load to the big material, and which in turn enhances in catalysis, biology doctor
The effect of in the application such as.HSN form and feature depends greatly on synthesis strategy, its in response to and it is different.
Hard template method (being known to be the conventional method for synthesizing hollow silicon dioxide nano-particle) be using solid and
Hard particles (such as polystyrene particle) are used as kernel templates, and mould material is heterogeneous for silica.Mirror
In this, kernel templates can be etched by calcining, solvent dissolving or other means, to be stayed in the silica shell body of closing
Under hollow space (Lee Y. (Li, Y.);Apply J. (Shi, J.), hollow-core construction mesoporous material:Chemical synthesis, functionalization and should
With (Hollow-structured mesoporous materials:chemical synthesis,
Functionalization and applications), advanced material (Adv Mater) 2014,26,3176-3205).Though
Homogeneity, Nanoparticle shape and the cavity dimension of right nano-particles size can be with precisely controlled, but this kind of method
Multi-step synthetic process and cumbersome template etching program are needed, this is time-consuming and/or complicated.
Soft template method is also using the kernel templates in etching core shell structure to form hollow silicon dioxide nano-particle
Design, but the template " softer " that kernel templates are more used than in hard template method.For example, soft kernel templates can be flexible
Property liquid " particle ", such as micella, emulsion, the vesica being made up of silica dissimilar materials, or even bubble.However, generally recognize
There is irregular outward appearance and wider size distribution because of the pliability of the soft template for the HSN prepared by these methods.
For example, if before Silica Shell structure is hardened, the oil in oil-in-water (O/W) type emulsion by mesoporous effusion,
To so special rounded cap sample HSN (Zou C.-J. (Tsou, C.-J.) be formed;Big vast Y. (Hung, Y.);Try to gain C.-Y. (Mou, C.-
Y.), thickness of shell and the adjustable hollow mesoporosity titanium dioxide as the application of wide scope pH nano-sensors of pore size distribution
Silicon nano (Hollow mesoporous silica nanoparticles with tunable shell
thickness and pore size distribution for application as broad-ranging pH
Nanosensor), micropore and mesoporous material (Microporous and Mesoporous Materials) 2014,190,181-
188)。
However, can not but load bioactive ingredients before template etching program, reason is that described program is possible to ruin
Going out, it is active.
In addition to the above method, architectural difference method for selective etching provides for synthesis hollow silicon dioxide nano-particle
Difference design.In this kind of method, the titanium dioxide with architectural difference is formed in nano-particle using different silica sources
Silicon nano, i.e. the structure shows varying strength in different loci, and specifically, internal layer is more fragile than outer layer.It is this existing
As being found in some sol-gel process, including most general Shi Tuobai methods (method).Therefore, choosing is passed through
Selecting property and light and slow the breakable bond removed in nano-particle will produce hollow space.The removing breakable bond phase of selectivity
It is controllable for, especially when particular design improves the degree of architectural difference during Nano particles of silicon dioxide manufactures
When.
(Chang) et al. has been disclosed for a kind of the advantages of synthesis by using in micro-emulsion systems and from the beginning (de
Novo the method that) enzyme is encapsulated in HSN (is used for the hollow silicon dioxide nanosphere for being encapsulated enzyme of intracellular biological catalysis
(Enzyme encapsulated hollow silica nanospheres for intracellular
Biocatalysis), American Chemical Society's application material and interface (ACS Appl Mater Interfaces) 2014,6,
6883-6890;The cell of hollow silicon dioxide nanosphere containing enzyme is implanted into as protein protective:Superoxide dismutase and
Cascade system (the Intracellular implantation of enzymes in hollow silica of catalyzing enzyme
nanospheres for protein therapy:cascade system of superoxide dismutase and
Catalase), small (Small) 2014,10,4785-4795).However, although architectural difference method for selective etching can be
Prevent in a way using hard template or soft template method problem encountered, but hollow silicon dioxide nano-particle
Yield it is very low (at most about 10mg/20mL oil).In addition, the nano-particle prepared by these methods still has the tendency of aggregation,
This is that have significant problem to be solved.
Therefore, it is still necessary to which improved hollow silicon dioxide nano-particle is as drug delivery system, and this kind of sky of synthesis
The cost-efficient straightforward procedure of heart Nano particles of silicon dioxide.
The content of the invention
In order to overcome the problem of being run into art, the application provides solution below.
A kind of Nano particles of silicon dioxide is provided, it belongs to hollow silicon dioxide nano-particle (HSN) and can especially filled
Work as drug delivery system.
First, the invention provides a kind of Nano particles of silicon dioxide, it includes multi-layer silica dioxide housing, wherein each
Housing has mesoporous gap and surrounds the hollow space of closing, wherein inner most closed hollow space optionally has solid dioxy
SiClx core;And one or more bioactive ingredients in the space are encapsulated in, wherein the chi of the bioactive ingredients
It is very little to be more than the pore-size for being encapsulated its housing, and the bioactive ingredients in wherein each space can be with identical or different.
Secondly, present invention also offers a kind of method for preparing Nano particles of silicon dioxide, comprise the steps of:
(a) any one of step (a-1) and (a-2):
(a-1) oil phase, surfactant, alkoxy silane and/or silicate source, wherein optional containing one or more is provided
The aqueous phase of kind bioactive ingredients and optional cosurfactant, to form Water-In-Oil (W/O) type microemulsion;With
(a-2) oil phase, surfactant, alkoxy silane and/or silicate source and optional cosurfactant are provided
Agent, to form mixture;
(b) into the W/O microemulsions of (a-1), addition triggers reagent, or the water-based initiation examination of mixture addition to (a-2)
Agent, to form Water-In-Oil (W/O) type microemulsion, be subsequently formed silica nanometer core, the silica nanometer core and its table
Bioactive ingredients on face are bonded and/or are encapsulated bioactive ingredients in wherein;
(c) aqueous phase containing bioactive ingredients is provided;
(d) alkoxy silane and/or silicate source are introduced, to form the another of the silica nanometer core of encirclement (b)
Individual silicon dioxide layer;
(e) step (c) and (d) are optionally repeated one or more times;
(f) stabilization removal condition is implemented so that W/O microemulsions stabilization removal and the gained that is thusly-formed by microemulsion of collection
Particle;And
(g) particle collected in step (f) is scattered in Aqueous wash phase, to obtain silica dioxide nano particle
Son;
Alkoxy silane and/or silicate source and the alcoxyl optionally in step (a) wherein in step (d) and (e)
Base silane and/or silicate source include at least one organoalkoxysilane, and
Wherein the size of bioactive ingredients is more than the pore-size for being encapsulated its Silica Shell.
Present invention also provides pass through the product prepared by the above method.
Brief description of the drawings
Fig. 1 (A) to 1 (F) is the TEM shadows of tester Nano particles of silicon dioxide and inventive silica nano-particle
Picture.
Fig. 2 (A) and 2 (B) is the nitrogen suction of inventive silica nano-particle, desorption isotherm.
Fig. 3 (A) and 3 (B) depict asparaginase, PEG- asparaginases and inventive silica nano-particle
Enzymatic activity test result.
Fig. 4 depicts MOLT-4 leukaemia and ties up to asparaginase, tester Nano particles of silicon dioxide and Ben Fa
Cytotoxicity analysis in the presence of bright Nano particles of silicon dioxide.
Fig. 5 (A) and (B) depict the cell absorption efficiency based on inventive silica nano-particle and analyzed (in MOLT-
In 4 cells) result.
Fig. 6 depicts free asparaginase, tester Nano particles of silicon dioxide and inventive silica nanoparticle
The test result of the ability of Apoptosis occurs for son induction MOLT-4 Leukemia Cell Lines.
Fig. 7 depicts the result that inventive silica nano-particle is removed from the mouse circulatory system.
Fig. 8 depicts the result that IVIS fluoroscopic imaging systems carry out bio distribution analysis to particle of the present invention.
Embodiment
In order to promote the understanding to disclosure herein, term as used herein is defined as follows hereby.
In the context of present specification and claims, unless otherwise expressly specified, an otherwise singulative " (a/
An) " and " (the) " includes multiple mentioned things.Unless otherwise stated, provided herein is any and all example
Or exemplary language (such as " such as ") is only used for the scope that the present invention is better described, is not intended to limit the present invention.
It will be appreciated that any number range described in this specification is intended to include all subranges wherein covered.Lift
For example, the scope of " 50 to 70 DEG C " includes all subranges and spy 50 DEG C of the minimum value between 70 DEG C of the maximum
Definite value, including such as 58 DEG C to 67 DEG C, and 53 DEG C to 62 DEG C, 60 DEG C or 68 DEG C.Due to disclosed number range be it is continuous,
Therefore it contains each numerical value between minimum value and maximum.Unless otherwise indicated, that is otherwise pointed out in this specification is each
Kind number range is approximate.
In the present invention, term " about " refers to be directed to the acceptable of set-point measured by those skilled in the art
Deviate, this depend partly on how to measure or determine described value.
In the present invention, unless illustrating, otherwise prefix " receiving (nano-) " as used herein mean about 300nm or
Smaller size.Unless illustrating, otherwise prefix " being situated between (meso-) " as used herein is different from the definition that IUPAC is proposed,
Mean about 5nm or smaller size.
In the present invention, as used herein, term " silane " refers to SiH4Derivative.Generally, in four hydrogen at least
The substituent displacement as described below of one quilt such as alkyl, alkoxy, amino etc..As used herein, term " alkoxy silane "
Refer to that there is at least one silane of the directly bond to the alkoxy substituent of silicon atom.As used herein, term " organic alcoxyl
Base silane " refers to directly bond at least one alkoxy substituent of silicon atom and the silicon of at least one hydrocarbyl substituent
Alkane.As used herein, term " silicate source " refers to that the salt form of positive silicic acid or the material of ester-formin, such as positive silicon can be considered as
Sour sodium, sodium metasilicate, tetraethyl orthosilicate (tetraethoxysilane, TEOS), positive quanmethyl silicate, positive silicic acid orthocarbonate.Optionally
Ground, hydrocarbyl substituent further can substitute or be mixed with through hetero atom.
In the present invention, as used herein, term " alkyl " refers to the monoradical derived from hydrocarbon.As used herein, art
Language " hydrocarbon " refers to a kind of molecule being only made up of carbon and hydrogen atom.Hydrocarbon example include but is not limited to (ring) alkane, (ring) alkene,
Alkadienes, aromatic hydrocarbon etc..When alkyl is further substituted as mentioned above, substituent can be halogen, amino, hydroxyl,
Mercapto etc..When alkyl is mixed with as mentioned above hetero atom, the hetero atom can be S, O or N.In the present invention,
Alkyl preferably comprises 1 to 30 C atoms.
In the present invention, term " alkyl " refers to the straight chain or branched-chain alkyl of saturation, and it is former that it preferably comprises 1-30 carbon
Son and more preferably 1-20 carbon atom.Examples of alkyl includes but is not limited to methyl, ethyl, propyl group, isopropyl, normal-butyl, secondary
Butyl, isobutyl group, the tert-butyl group, 2- ethyl-butyls, n-pentyl, isopentyl, 1- methyl amyls, 1,3- dimethylbutyls, n-hexyl,
1- methylhexyls, n-heptyl, different heptyl, 1,1,3,3- tetramethyl butyls, 1- methylheptyls, 3- methylheptyls, n-octyl, 2- second
Base hexyl, 1,1,3- trimethyls, 1,1,3,3- tetramethyls amyl group, nonyl, decyl, undecyl, 1- methylundecyls,
Dodecyl, 1,1,3,3,5,5- hexamethyls hexyl, tridecyl, myristyl, pentadecyl, cetyl, heptadecyl,
Octadecyl or its analog.
In the present invention, as used herein, term " alkoxy (alkoxyl) " or " alkoxy (alkoxy) " mean have
The group of formula "-O- alkyl ", wherein the definition of " alkyl " in the formula has the implication of " alkyl " as described above.
In the present invention, as used herein, term " cycloalkyl " means containing 3 to 10 ring carbon atoms and more preferably 3 to 8
The saturation or part unsaturated cyclic carbon-based group of individual ring carbon atom, the ring-type carbon-based group substitute optionally on ring containing alkyl
Base.Examples of cycloalkyl includes but is not limited to cyclopropyl, cyclopropanyl, cyclobutyl, cyclopenta, cyclohexyl, 2- cyclohexene -1- bases
With and the like.
In the present invention, term " halogen " or " halogen " represent fluorine, chlorine, bromine or iodine.
In the present invention, as used herein, term " amino " means formula-NR1R2Functional group, wherein R1And R2Each solely
On the spot represent hydrogen or alkyl as defined above.
In the present invention, as used herein, term " aqueous phase " means the phase substantially miscible with water.Aqueous phase example includes
(but not limited to) water in itself, aqueous buffer solution, dimethyl sulfoxide (DMSO) aqueous solution, the alkanol aqueous solution etc..It can be based on to synthesis
And/or the demand of the stability for the material being present in aqueous phase adjusts aqueous phase so as in acid, neutral or alkalescence.
In the present invention, as used herein, term " oil phase " means to be substantially immiscible with aqueous phase as mentioned above
Phase.Oil phase example includes but is not limited to liquid (ring) alkane for being substituted or being unsubstituted, such as hexane, decane, octane, ten
Dioxane, hexamethylene etc.;The aromatic solvent for being substituted or being unsubstituted, such as benzene,toluene,xylene.
In the present invention, as used herein, term " bioactive ingredients " refers to active material in organism.
The example of bioactive ingredients includes but is not limited to enzyme, pharmaceutical grade protein, antibody, vaccine, antibiotic or nucleotides medicine.
It is encapsulated the hollow silicon dioxide nano-particle of bioactive ingredients
In an aspect, the invention provides a kind of Nano particles of silicon dioxide, and it is included:Multi-layer silica dioxide shell
Body, wherein each housing has mesoporous gap and surrounds the hollow space of closing, inner most closed hollow space optionally has
Solid silica core, the silica core have mesoporous gap;And it is encapsulated in one or more lifes in the space
The size of thing active component, wherein bioactive ingredients is more than the pore-size for being encapsulated its housing, and in wherein each space
Bioactive ingredients can be with identical or different.
In one embodiment of the Nano particles of silicon dioxide of the present invention, it, which has, contains nanometer core and at least one envelope
The core shell structure of closed shell body, and there is space between nanometer core and housing.In one embodiment, nanometer core is solid.
In another embodiment, nanometer core is hollow and thus can also be considered as the hollow shell of closing.In one embodiment,
Nano particles of silicon dioxide has a hollow Nano core and a shell, i.e. two closing housings altogether.In another implementation
In example, Nano particles of silicon dioxide has a solid nanometer core and the shell of a closing.In one embodiment, titanium dioxide
Silicon nano has a hollow core and two or more closing housings, i.e. total of three or more closing housing.
In another embodiment, Nano particles of silicon dioxide has a solid nanometer core and two or more closures.
The granularity of the hollow silicon dioxide nano-particle of the present invention is defined according to the external diameter of the outermost layer housing of closing.
In one embodiment, the particle size range of Nano particles of silicon dioxide of the invention is about 20mm to about 500nm, preferably from about 20nm
To 150nm, more preferably less than 100nm or less than 30nm.
In one embodiment, the housing of Nano particles of silicon dioxide of the invention independently of one another have at least about 2nm,
At least about 3nm or at least about 5nm;And at most about 15nm, at most about 12nm or at most 10nm thickness;Or thickness is on foregoing
In the range of limit and any combinations of lower limit are formed.
The present invention hollow silicon dioxide nano-particle nanometer core and housing have it is mesoporosity, and mesoporous gap have about
5nm or smaller, preferably 3nm or smaller, more preferably 2nm or smaller size.
In one embodiment, each housing surrounds the hollow space of closing, and between nanometer core and housing or each shell
The distance between body is less than 75nm, preferably about in the range of 2nm to 75nm, more preferably about in the range of 2nm to 50nm.
In one embodiment, the outer surface of housing and inner surface can be independently unmodified or through modification.Shell
From the beginning the modification in body surface face (de novo) can be carried out or modified after being.The example of modification can be (but are not limited to) parent
Water-based modification, such as PEG (PEG) modification, polyethyleneimine (PEI) modification, 3- (ortho-siliformic acid base) hydroxypropyl methyl phosphine
Acid esters (THPMP) modification, N- (trimethoxysilylpropyl) ethylenediamine triacetic acid (EDTAS) modification, N- [3- (trimethoxies
Silylation) propyl group] ethylene diamine-modified, N- [3- (trimethoxy silane base) propyl group]-N, N, N- trimethyl ammoniums (TA- trimethoxies
Silane) modification, (3- mercaptopropyis) trimethoxy silane (MPTMS) modification, amphoteric ion type it is hydride modified;Special sex modification,
Such as biomarker modification, such as the modification of antibody modification, linking group, ligand modification of target tumor etc.;It is or non-specific living
Sex modification, such as the modification of surface of shell characteristic, such as modification of charge type or distribution etc..
Hollow silicon dioxide nano-particle includes one or more bioactive ingredients being encapsulated in space.In an implementation
In example, bioactive ingredients are encapsulated between each housing.In one embodiment, hollow silicon dioxide nano-particle has one
Individual solid nanometer core and the shell of a closing, and bioactive ingredients are encapsulated in nanometer between core and housing.In another reality
Apply in example, for nanometer core and outermost housing, bioactive ingredients may be coupled to its surface.In one embodiment
In, the size of bioactive ingredients is more than the size of mesoporous gap.In other embodiments, size is less than or equal to the volume of mesoporous gap
From the beginning outer therapeutic agent (de novo) can be loaded or be passively loaded into hollow silicon dioxide nano-particle.
In one embodiment, bioactive ingredients can be selected from water miscible bioactive ingredients or carry out table
The bioactive ingredients can be dispersed or dissolved in aqueous phase are modified in face.In one embodiment, bioactive ingredients be enzyme,
Pharmaceutical grade protein, antibody, vaccine, antibiotic or nucleotides medicine.The example of enzyme includes but is not limited to Ah add'sing carbohydrase
(agalsidase), Imiglucerase (imiglucerase), his sharp glycosides enzyme (taliglucerase), Wella glycosides enzyme
(velaglucerase), alglucerase (alglucerase), Sai Beili enzymes (sebelipase), La Luoni enzymes
(laronidase), Chinese mugwort Du sulphur enzyme (idursulfase), angstrom Lip river sulphur enzyme (elosulfase), plus sulphur enzyme (galsulfase), Ah
Glucosidase (alglucosidase), asparaginase (asparaginase), glutaminase (glutaminase), smart ammonia
The de- imines enzyme (arginine deiminase) of acid, arginase (arginase), methioninase (methioninase), half
Cystine enzyme (cysteinase), Homocysteine desulfurase (homocysteinase), PAH, Phenylalanine ammonia split
Solve enzyme, urate oxidase, catalyzing enzyme, HRPO, superoxide dismutase or glutathione peroxidase.
The example of other therapeutic agents include but is not limited to cranberry (doxorubicin), curcumin (curcumine),
Paclitaxel (paclitaxel), Ipsapirone (ixabepilone), gemcitabine (gemcitabine), Irinotecan
(irinotecane), SN-38,5-FU, daunomycin (daunorubicin), docetaxel (docetaxel) etc..
Without being bound by theory, Nano particles of silicon dioxide of the invention shows about 400m2/ g or smaller (such as 50 arrive
200m2/ g) BET surface area, this depend on be encapsulated bioactivator type and amount, Nano particles of silicon dioxide housing
The number of the multilayer of layer on surface and modification.
The Nano particles of silicon dioxide of the present invention can be prepared by (but not limited to) architectural difference method for selective etching.
Preferably, Nano particles of silicon dioxide of the invention is not calcined during preparation.In consideration of it, the silica nanometer of the present invention
Particle preferably has organic silica residue, such as organoalkoxysilane in the surface of nanometer core and closing housing or above
Residue.
It is encapsulated the preparation method of the Nano particles of silicon dioxide of bioactive ingredients
The present invention also provides a kind of method for the Nano particles of silicon dioxide for preparing and being wherein encapsulated bioactive ingredients.It is described
Method comprises the steps of:
(a) any one of step (a-1) and (a-2):
(a-1) oil phase, surfactant, alkoxy silane and/or silicate source, wherein optional containing one or more is provided
The aqueous phase of kind bioactive ingredients and optional cosurfactant, to form Water-In-Oil (W/O) type microemulsion;With
(a-2) oil phase, surfactant, alkoxy silane and/or silicate source and optional cosurfactant are provided
Agent, to form mixture;
(b) into the W/O microemulsions of (a-1), addition triggers reagent, or the water-based initiation examination of mixture addition to (a-2)
Agent, to form Water-In-Oil (W/O) type microemulsion, be subsequently formed silica nanometer core, the silica nanometer core and its table
Bioactive ingredients on face are bonded and/or are encapsulated bioactive ingredients in wherein;
(c) aqueous phase containing bioactive ingredients is provided;
(d) alkoxy silane and/or silicate source are introduced, to form the another of the silica nanometer core of encirclement (b)
Individual silicon dioxide layer;
(e) step (c) and (d) are optionally repeated one or more times;
(f) stabilization removal condition is implemented so that W/O microemulsions stabilization removal and the gained that is thusly-formed by microemulsion of collection
Particle;And
(g) particle collected in step (f) is scattered in Aqueous wash phase, to obtain silica dioxide nano particle
Son;
Alkoxy silane and/or silicate source and the alcoxyl optionally in step (a) wherein in step (d) and (e)
Base silane and/or silicate source include at least one organoalkoxysilane, and
Wherein the size of bioactive ingredients is more than the pore-size for being encapsulated its Silica Shell.
In step (a-1), the amount of oil phase, surfactant and aqueous phase is selected, so as to the shape after these material mixings
Into Water-In-Oil (W/O) type microemulsion.In general, in order to form W/O microemulsions, the amount of oil phase is than surfactant and aqueous phase
Measure much bigger.The mode of W/O microemulsions is formed in the art it is generally known that and can use in the present invention living to biology
The active lossless mode of property composition.Oil phase, aqueous phase, bioactive ingredients, definition and the reality of alkoxy silane and silicate source
Example has described in detail as above.
Surfactant for forming W/O microemulsions is conventional and well known in the art.The present invention preferably makes
Use nonionic surface active agent.Including but not limited to poly- (ethylene oxide) nonyl benzene of example of nonionic surface active agent
Base ether (such as CO-520), polyoxyethylene glycol sorbitan alkyl esters, polyethylene glycol alkyl ether, glucoside alkyl ether,
Triton X-100, polyalkylene glycol alkyl phenyl ether, alkyl esters of glycerol, polypropylene glycol alkyl ether, poloxamer
(poloxamer), coconut oleoyl amine MEA (coconut oleoyl amine MEA), cocamide diethanolamine (coconut oleoyl amine DEA), bay
Base dimethylamine oxide, polyethoxylated tallow amine etc..
It is optionally possible to promote formation or the microemulsion of microemulsion using cosurfactant.Auxiliary surface is lived
The example of property agent includes but is not limited to alkanols, such as hexanol, polyethylene glycol 400 (PEG 400), PEG 600 etc..
A small amount of cosolvent can be introduced into aqueous phase to reach the fine dispersion of bioactive ingredients or dissolving if necessary.Altogether
The example of solvent includes but is not limited to dimethyl sulfoxide (DMSO), ethanol, PEI, PEG, polylysine, poly arginine, arginine
Solution, glutamate solution, arginine-glutamic acid mixed salt solution, single candy, double candys, few candy, polysaccharide, sodium chloride, potassium chloride,
Sodium sulphate, Tris buffer solutions, phosphate buffer etc..
In one embodiment, in step (a-1), wherein the optional aqueous phase containing one or more bioactive ingredients
It is to be provided before alkoxy silane and/or silicate source.In another embodiment, in step (a-1), alkoxy silane
And/or silicate source is that the optional aqueous phase containing one or more bioactive ingredients provides before wherein.Again another
In embodiment, in step (a-1), wherein optional aqueous phase and alkoxy silane containing one or more bioactive ingredients
And/or silicate source provides simultaneously.That is, the aqueous phase containing one or more bioactive ingredients and alkoxy silane and/or silicic acid
The order that Yanyuan is introduced in the step (a) is tradable or simultaneously.
In another embodiment, using step (a-2);That is, there is provided oil phase, surfactant, alkoxy silane and/
Or silicate source and optional cosurfactant, to form mixture.
Then, reagent is triggered to trigger the formation of silica as step (b), addition.In step (b), trigger examination
Agent is a kind of material that can be triggered silica and form reaction.The example of reagent is triggered to include but is not limited to acidic materials,
Such as acid or acidic aqueous solution, such as hydrochloric acid, sulfuric acid etc.;Alkaline matter, such as alkali or alkaline aqueous solution, such as ammoniacal liquor, sodium hydroxide water
Solution;And ion gun, such as the solution of salt, salt and buffer, such as sodium fluoride, PB etc..In one embodiment
In, when using step (a-2), the introduced initiation reagent is water-based initiation reagent in step (b), and it is not only triggered
The formation of w/o type microemulsion, also trigger silica and form reaction.Reaction forms silica nanometer core after initiation, its
Middle bioactive ingredients are connected to the surface of silica nanometer core and/or are encapsulated in silica nanometer core.
In one embodiment, when the aqueous phase used in step (a-1) does not include bioactive ingredients, step (b)
Formed in silica nanometer core be not connected to and/or be encapsulated at the very start any bioactive ingredients.In an implementation
In example, when in step (a-1) using the aqueous phase containing bioactive ingredients, the silica nanometer formed in step (b)
Core will be connected to and/or be encapsulated bioactive ingredients.
In follow-up step (c) and (d), another aqueous phase containing bioactive ingredients and another alkoxy are introduced respectively
Silane and/or silicate source.Then, another silicon dioxide layer for surrounding silica nanometer core is formed, this then makes dioxy
SiClx particle becomes double-deck.
, can optionally further repeat step (c) and (d) as step (e) after double-deck silicon dioxide granule is formed
Operation one or more times, to form one or more the extra layers (such as the three, 4th ... etc. for surrounding existing silicon dioxide granule
Layer).
Then, as step (f), implementation makes the condition of W/O microemulsion stabilization removals and collected to be thusly-formed by microemulsion
Gained particle.The example of stabilization removal condition including but not limited to adds stabilization removal agent, such as alcohol, excess surface active agent
Deng.Collected particle can be quickly with water, alkanols (such as C1-3Alcohol, such as ethanol, isopropanol) or water-based alkanols solution
Rinse.
Finally, as step (g), particle collected in step (f) is scattered in Aqueous wash phase, wanted with obtaining
The Nano particles of silicon dioxide asked.Washing can be mutually water, alkanols (such as C1-3Alcohol, such as ethanol, isopropanol) or water-based alkanol
Class solution.
There is mesoporous gap in its surface by the nm core obtained by the method for the present invention and layer.It is without being bound by theory,
It can be adjusted by using different types of surfactant, cosurfactant and/or alkoxy silane and/or silicate source
The size of whole mesoporous gap.
Preferably, the cumulative volume of the surfactant used in this method and cosurfactant is to alkoxy silane
And/or the ratio of the overall machine of silicate source is through control.In one embodiment, the ratio is at least 3.5:1, preferably at least
It is about 4.5:1, more preferably at least about 5.5:1;Or up to about 9.0:1, preferably up to about 8.0:1, more preferably up to
About 7.5:1;Or the ratio falls within the scope that foregoing arbitrary proportion is formed.
In one embodiment, when using step (e), i.e. provide and introduce the additional water containing bioactive ingredients
When mutually with alkoxy silane and/or silicate source, the number of housing can be adjusted in step (g) according to the expectation of implementer
Mesh.Determine that the factor of housing number includes repeating (c) and (d) number, in those steps alkoxy silane used
And/or the type of silicate source, the wash time in step (g), temperature for being washed in step (g) etc..For example, when
When Nano particles of silicon dioxide has double-decker, step (e) need to be carried out at least once.In one embodiment, step is carried out
(e) once, producing after washing only has the Nano particles of silicon dioxide of individual layer.In addition, the temperature and/or time of washing can
The tolerance of washing is determined based on alkoxy silane and/or silicate source.For example, when temperature is higher, washing
Effect may be more obvious, and vice versa.The temperature of washing may be, for example, at most 80 DEG C, at most 70 DEG C etc., or can be environment temperature
Spend (20 DEG C, 25 DEG C or 37 DEG C).In one embodiment, after washing, silica nanometer core remains solid, forms simultaneously
Surround one or more housings of silica nanometer core and the hollow space of closing.In one embodiment, each layer (including two
Silica nanometer core) it is the housing for surrounding the hollow space closed.
In one embodiment, step (a), (d) and alkoxy silane used in (e) and/or silicate source are each only
It is on the spot identical or different.In one embodiment, alkoxy silane and/or silicate source include tetraethoxysilane
(TEOS), tetramethoxy-silicane (TMOS), sodium metasilicate or its mixture.In one embodiment, organoalkoxysilane is 2-
[methoxyl group (polyethyleneoxy) propyl group]-trimethoxy silane (PEG- trimethoxy silanes), 3- aminopropyl trimethoxy silicon
Alkane (APTMS), propyl-triethoxysilicane, butyl trimethoxy silane, octyl group trimethoxy silane, diphenyl diethoxy silicon
Alkane, n-octytriethoxysilane, mercaptopropyi trimethoxy silane, chloromethyl trimethoxy silane, isobutyl group triethoxy
Silane, APTES, ethyl trimethoxy styrene silane, MTES, the second of phenyl three
TMOS (PTEOS), phenyltrimethoxysila,e (PTMOS), MTMS (MTMOS), ethyl triacetyl oxygen
Base silane (ETAS), N- (trimethoxysilylpropyl) ethylenediamine triacetic acid (EDTAS), (3- ortho-siliformic acids base) propyl group first
Base phosphonate ester (THPMP), methyl triacetoxysilane (MTAS), N- [3- (trimethoxy silane base) propyl group] ethylenediamine, three
Methoxy silane base propyl group (polyethyleneimine), chlorination N- trimethoxysilylpropyls-N, N, N- trimethyl ammonium, (3- sulfydryls
Propyl group) trimethoxy silane (MPTMS), amphoteric ion type silane or its mixture.In one embodiment, alkoxy silane
And/or silicate source is TEOS and APTMS mixture, THPMP, APTMS and TEOS mixture, or EDTAS, APTMS with
TEOS mixture.In one embodiment, alkoxy silane and/or silicate source used in step (a) be THPMP,
APTMS and TEOS mixture;Or EDTAS, APTMS and TEOS mixture.In one embodiment, step (d) and/or
(e) alkoxy silane and/or silicate source used are APTMS and TEOS mixture in.
The present invention also provides the Nano particles of silicon dioxide prepared by any method as described above.
Following instance is in order to which those skilled in the art in the invention know more about the present invention and provide, but is not intended to limit
The scope of the present invention processed.
Example
Material, method and test model
The asparaginase (PEG- asparaginases) modified through PEG
As known in art, asparaginase (" ASNases ") is applied to the treatment white blood of Acute Lymphoblastic
Sick (ALL) patient.Therefore, asparaginase is used as an example of the bioactive ingredients of the present invention.In order to improve asparagus fern acyl
Solubility of the amine enzyme in aqueous phase, we modify the surface of asparaginase with SCM-PEG-MPTMS parts;The product exists
Hereinafter referred to as PEG- asparaginases.It is without being bound by theory, it is believed that PEG- asparaginases can with alkoxy silane and/or
Silica source combines altogether and this combine altogether can aid in that PEG- asparaginases are subsequent to be encapsulated.PEG- asparaginases
Preparation be described as follows:By maleimide-PEG-succimide base ester (MAL-PEG-SCM) (6.4mg)
(3- mercaptopropyis) trimethoxy silane (MPTMS) (5 μ L) is mixed with asparaginase (1mg), and mixture is dissolved in
NaH2PO4In cushioning liquid (50mM, pH 7.8) and in 4 DEG C of agitating solutions 6 hours.Then, by 4 DEG C in NaH2PO4It is slow
Rush in solution (50mM, pH 7.8) dialysis 2 days and the product (PEG- asparaginases) is purified with unnecessary reagent.Finally useUltrafilter concentrates PEG- asparaginases.
The asparaginase of fluorogen mark
In the analysis based on fluorescence, asparaginase can be combined with fluorogen;Here, for example if isothiocyanic acid is red
Bright (RITC) or fluorescein isothiocynate (FITC).RITC mark PEG- asparaginases synthesis can by similar to
RITC and MAL-PEG-SCM and MPTMS are concomitantly introduced into by the method for PEG- asparaginase synthetic methods to complete, and
Itself and asparaginase covalent bond can also be made.
Transmission electron microscope (TEM)
Assessed using transmission electron microscope (TEM) and directly check the outward appearance of Nano particles of silicon dioxide, such as each layer
Size, the number of housing and thickness, the dimension of hollow space etc. of closing.Pass through the Hitachi operated under 75kV accelerating potentials
H-7100 transmission electron microscopes obtain TEM images, and sample dispersion is subsequently deposited within ethanol and sonicated 30 seconds
Dry on copper mesh through carbon coating and in atmosphere.
Dynamic light scattering (DLS)
On Malvern Zetasizer Nano ZS (Malvern, UK), using dynamic light scattering (DLS) to different molten
Nano particles of silicon dioxide in pendular ring border carries out dimensional measurement.The concentration of Nano particles of silicon dioxide is 0.2-0.3mg/mL.
Analyze (solvation) granularity in different solutions:H2O (pH 6~7), the Du Erbeikeshi containing 10% hyclone (FBS) change
Good figure eagle culture medium (Dulbecco's Modified Eagle Medium, DMEM), the Dole shellfish containing 20%FBS
Coriolis modified form eagle culture medium (DMEM), the RPMI culture mediums 1640 containing 10%FBS, and PBS cushioning liquid (pH
7.4)。
Asparaginase activity for sign is tested
Utilize Nesslerization (Nesslerization method) (Ma Xieben, L.T. by detecting ammonia
(Mashburn, L.T.) and Switzerland, J.C. (Wriston, J.C.), biochemistry and biophysical studies communication
(Biochemical and biophysical research communications), 1963,12 (1), 50-55), to day
Winter lactamase activity carries out qualitative assessment.Specifically, by asparaginase or silica nanometer containing asparaginase
Particle is centrifuged and is scattered in 200 μ L 0.05M Tris buffer solutions (pH 8.6) respectively, and then with it by matter (that is, 1.7mL
The 0.05M Tris buffer solutions containing 0.01ML- asparagines, pH 8.6;Altheine is purchased from Pro-Spec) exist together
Cultivated 10 minutes to 72 hours at 37 DEG C;The parallel control group for being not added with asparaginase is cultivated in the same terms.Pass through addition
100 μ L 1.5M trichloroacetic acids (TCA) react to be quenched.Then sample is centrifuged, and with 7mL deionized water (18.2M
Ω resistivity) dilute 500 μ L of supernatant liquid and (be purchased from Merck & Co., Inc. with 1mL nessler's reagent (Nessler's reagent)
(Merck);Contain potassium hydroxide and potassium tetraiodomercurate) mix and form flaxen solution (containing ammonia).Train at room temperature
Educate mixture 10 minutes, and brightness is inhaled with spectrometer measurement 480nm.Ammonium sulfate is used as reference material to establish calibration curve.1 work
Property unit (U) asparaginase be defined as asparaginase ammonia caused by 37 DEG C, pH 8.6 times amount (micromole/point
Clock/milligram).
Synthesize example 1
PEG-HSN synthesis
Example 1A:PEG- asparaginase@PEG-HSN 15
Using 20mL decane (as oil phase), 3.5mL CO-520 (as surfactant) and 1.1mL hexanols (as optional
Cosurfactant) mixing.Then, 200 μ L TEOS and 25 μ L APTMS ethanol solutions (are come from and contains 200 μ L
The liquid storage of APTMS 1.4mL ethanol) it is added to (as alkoxy silane and/or silica source) in mixture and at 20 DEG C
Lower stirring mixture.After 15 minutes, by 500 μ L NH4OH (28-30wt.%) is added dropwise to mixing (as reagent is triggered)
In thing, to trigger silica alkoxy silane and/or silica source that hydrolysis and formation silica nanometer core occurs.2 is small
Shi Hou, 700 μ L H are slowly added into microemulsion2O (wherein containing 2385.2 μ g PEG- asparaginases, as aqueous phase).Again
After spending 10 minutes, added into microemulsion 300 μ L TEOS and 100 μ L APTMS ethanol solutions (as alkoxy silane and/or
Silica source) and 12 hours second silica that silica nanometer core is surrounded with formation of stirring microemulsion at 20 DEG C
Layer.Then, both 500 μ L PEG- trimethoxy silanes and 50 μ L TEOS are added to modify the table of Nano particles of silicon dioxide
Face.After 24 hours, using 95% ethanol by micro-emulsion systems stabilization removal.Received by centrifuging 25 minutes under 15,500rpm
Collection gained particle and with the quick rinse of ethanol.Then, by particle transfer into 200mL deionized waters, it is small that 2 are washed at 50 DEG C
When.Finally, hollow silicon dioxide nano-particle (HSN) is formed, collects and is washed twice with ethanol by centrifuging.Finally by institute
Product (PEG- asparaginase@PEG-HSN 15) is stated to disperse and store in 99.5% ethanol.PEG- asparaginases are encapsulated
In space between internal layer and outer layer.
Example 1B:It is hollow that the control group without asparaginase is prepared using the similar program as described in above-mentioned example 1A
Nano particles of silicon dioxide (PEG-HSN 18), makes an exception not contain asparaginase in aqueous phase.
Example 1C:PEG- asparaginase@PEG-HSN 10
Using 20mL decane (as oil phase), 3.5mL CO-520 (as surfactant) and 1.1mL hexanols (as optional
Cosurfactant) mixing.Then, 350 μ L are contained to the H of 669.5 μ g PEG- asparaginases2O is added in solution
(as the aqueous phase containing bioactive ingredients).After 2 minutes, 200 μ L TEOS and 25 μ L APTMS ethanol solutions (are come self-contained
Have the liquid storage of 200 μ L APTMS 1.4mL ethanol) it is added to (as alkoxy silane and/or silica source) in microemulsion
And stir microemulsion at 20 DEG C.After 15 (15) minutes, by 500 μ L NH4OH (28-30wt.%) (as trigger reagent) by
Drop is added in microemulsion, to trigger silica alkoxy silane and/or silica source that hydrolysis and formation titanium dioxide occurs
Silicon nanometer core.After 2 hours, the H that 350 μ L contain 669.5 μ g PEG- asparaginases is slowly added into microemulsion2O (as
Aqueous phase containing bioactive ingredients).After 10 minutes, 300 μ L TEOS and 100 μ L APTMS second are added into microemulsion
Alcoholic solution (as alkoxy silane and/or silica source) and microemulsion 12 hours is stirred at 20 DEG C surround dioxy to be formed
Second silicon dioxide layer of SiClx nanometer core.Then, add both 500 μ L PEG- trimethoxy silanes and 50 μ L TEOS with
Modify the surface of Nano particles of silicon dioxide.After 24 hours, using 95% ethanol by micro-emulsion systems stabilization removal.By
25 minutes are centrifuged under 15,500rpm to collect gained particle and with the quick rinse of ethanol.Then, particle transfer is gone to 200mL
In ionized water, washed 2 hours at 50 DEG C.Finally, hollow silicon dioxide nano-particle (HSN) is formed, is collected by centrifuging
And washed twice with ethanol.Finally by the product (PEG- asparaginase@PEG-HSN 10) be scattered in 99.5% ethanol and
Storage.PEG- asparaginases are encapsulated in the space in the space in internal layer and between internal layer and outer layer.
The synthesis for the PEG-HSN that surface is modified through TA- trimethoxy silanes
Example 1D:PEG- asparaginase@PEG-HSN 17
Surface is prepared through TA- trimethoxy silanes using chlorination N- [3- (trimethoxy silane base) propyl group]-trimethyl ammonium
The Nano particles of silicon dioxide of modification is described as follows.Using 20mL decane (as oil phase), 3.5mL CO-520 (as surface-active
Agent) and 1.1mL hexanols (as optional cosurfactant) mixing.Then, by 200 μ L TEOS and 25 μ LAPTMS ethanol
Solution (liquid storage from the 1.4mL ethanol containing 200 μ L APTMS) (as alkoxy silane and/or silica source) adds
Mixture is stirred into mixture and at 20 DEG C.After 15 minutes, 500 μ L NH are added dropwise into mixture4OH(28-
30wt.%) (as reagent is triggered) to trigger silica alkoxy silane and/or silica source that hydrolysis occurs and form two
Silica nanometer core lasts 2 hours.After silica alkoxy silane and/or silica source hydrolysis, 100 μ L chlorinations N- are introduced
[3- (trimethoxy silane base) propyl group]-trimethyl ammonium (TA- trimethoxy silanes, 95%) and stirring 2 hours.Then, Xiang Wei
700 μ L H are slowly added in emulsion2O (wherein containing 2385.2 μ g PEG- asparaginases, as aqueous phase).After 10 minutes
Afterwards, 300 μ L TEOS and 100 μ L APTMS ethanol solutions are added into microemulsion (as alkoxy silane and/or silica
Source) and 12 hours second silicon dioxide layers that silica nanometer core is surrounded with formation of stirring microemulsion at 20 DEG C.Then,
Both 500 μ L PEG- trimethoxy silanes and 50 μ L TEOS are added to modify particle external surface.After 24 hours, 95% second is used
Alcohol is by micro-emulsion systems stabilization removal.Particle is collected by centrifuging 25 minutes under 15,500rpm and with the quick rinse of ethanol.
Then particle transfer is washed 2 hours into 200mL deionized waters and at 50 DEG C.Finally, HSN is formed, passes through centrifugation
To collect and be washed twice with ethanol.The product (PEG- asparaginase@PEG-HSN 17) is finally stored up in 99.5% ethanol
Deposit.
Example 1E:It is hollow that the control group without asparaginase is provided using the similar program as described in above-mentioned example 1D
Nano particles of silicon dioxide (PEG-HSN 19), make an exception to be free of asparaginase in aqueous phase.
Example 1F:PEG- asparaginase@PEG-HSN 11
Surface is prepared through TA- trimethoxy silanes using chlorination N- [3- (trimethoxy silane base) propyl group]-trimethyl ammonium
The Nano particles of silicon dioxide of modification is described as follows.Using 20mL decane (as oil phase), 3.5mL CO-520 (as surface-active
Agent) and 1.1mL hexanols (as optional cosurfactant) mixing.Then, 350 μ L are contained into 669.5 μ g PEG- asparagus ferns
The H of amidase2O is added in mixture (aqueous phase containing bioactive ingredients).After 2 minutes, by 25 μ L chlorinations N- [3- (three
Methoxy silane base) propyl group]-trimethyl ammonium (TA- trimethoxy silanes, 95%) is introduced into microemulsion.Then, by 200 μ L
TEOS and 25 μ L APTMS ethanol solutions (the 1.4mL ethanol containing 200 μ L APTMS) are (as alkoxy silane and/or dioxy
SiClx source) it is added in microemulsion and stirs microemulsion at 20 DEG C.After 15 minutes, 500 μ L are added dropwise into microemulsion
NH4OH (28-30wt.%) (as reagent is triggered) is to trigger silica alkoxy silane and/or silica source that water occurs
Solve and form silica nanometer core and last 2 hours.After silica alkoxy silane and/or silica source hydrolysis, introduce
25 μ L chlorinations N- [3- (trimethoxy silane base) propyl group]-trimethyl ammoniums (TA- trimethoxy silanes, 95%) and stirring 2 hours.
Then, 350 μ L H are slowly added into microemulsion2O (wherein containing 669.5 μ g PEG- asparaginases, as aqueous phase).Again
After spending 10 minutes, added into microemulsion 300 μ L TEOS and 100 μ L APTMS ethanol solutions (as alkoxy silane and/or
Silica source) and 12 hours second silica that silica nanometer core is surrounded with formation of stirring microemulsion at 20 DEG C
Layer.Then, both 500 μ L PEG- trimethoxy silanes and 50 μ L TEOS are added to modify particle external surface.After 24 hours, make
With 95% ethanol by micro-emulsion systems stabilization removal.Collect particle by centrifuging 25 minutes under 15,500rpm and use ethanol
Quick rinse.Then particle transfer is washed 2 hours into 200mL deionized waters and at 50 DEG C.Finally, HSN is formed,
Collect and washed twice with ethanol by centrifuging.The product (PEG- asparaginase@PEG-HSN 17) finally exists
Stored in 99.5% ethanol.PEG- asparaginases are encapsulated in the space in the space in internal layer and between internal layer and outer layer
It is interior.
It is encapsulated bioactive ingredients and the PEG-HSNs with individual layer is also made using different wash conditions.
The product particles yield obtained by these synthesis programs is individually about 100mg/20mL oil.
Example 2
TEM and DLS measurements
TEM measurements are carried out to the hollow silicon dioxide nano-particle synthesized in such as example 1 and result is depicted in Fig. 1.Can
Double-layer hollow Nano particles of silicon dioxide is successfully made to observe, the hollow space that each of which stratum boundary is closed surely.Grain
Degree and its standard deviation go out to be shown in Table 1.
Table 1
TEM results show that PEG- asparaginase@PEG-HSN 10,11,15 and 17 have being averaged for about 60nm to 95nm
Particle size and less granulometry are poor, which reflects the homogeneity of particle and disclosed in this invention preparation method it is excellent
Gesture.
The granularity of the hollow silicon dioxide nano-particle measured by dynamics light scattering (DLS) in different solutions environment
Go out to be shown in Table 2.
Table 2
Unit:nm
DLS results show that PEG-HSN 18 and 19 and PEG- asparaginase@PEG-HSN 10,11 and 15 are about
It is well dispersed within the range of 60nm to about 110nm in the culture medium containing serum, this is considered as being very suitable for cell suction
Receive.Although PEG- asparaginase@PEG-HSN 17 granularity expand (may because the particle zeta potential caused by surface modification is high and
Cause), but the size of particle is still acceptable for cell absorption.
Nitrogen suction, desorption isotherm and BET surface area
Fig. 2 depict PEG- asparaginase@PEG-HSN 15 and PEG- asparaginase@PEG-HSN 17 nitrogen inhale,
Desorption isotherm.According to thermoisopleth, PEG- asparaginase@PEG-HSN 15 and PEG- asparaginase@PEG-HSN have been disclosed
17 BET surface area is 117.40m respectively2/ g and 120.00m2/g。
Example 3
In order to assess the potential therapeutic action of Nano particles of silicon dioxide, gained freedom asparaginase using the above method
With the enzymatic activity of asparaginase being encapsulated in Nano particles of silicon dioxide.
Fig. 3 (A) depicts the enzymatic activity result of free asparaginase and PEG- asparaginase.It was observed that free asparagus fern
Amidase presents similar enzymatic activity with the asparaginase through modification, it means that in order to improve water-soluble and PEG- asparagus ferns
Between amidase and silica source with reference to probability and the asparagine Surface modification of enzyme that carries out does not interfere with asparaginase
Activity.
Fig. 3 (B) depicts PEG- asparaginases, PEG- asparaginase@PEG-HSN 15 and PEG- asparaginases@
PEG-HSN 17 enzymatic activity result.It was observed that as according to 10 minutes or 1 hour test measured by, PEG- asparaginases@
PEG-HSN 15 is similar with PEG- asparaginase@PEG-HSN 17 enzymatic activity.These results, which disclose, to be encapsulated in HSN
Asparaginase activity significant change does not occur, ensure that Nano particles of silicon dioxide in the treatment, in enzymatic activity table
Up to when validity.
Example 4
Trypsin resistance is analyzed
As known in art, one of side effect of asparagine enzyme therapy is acute pancreatitis, and it causes pancreas to be released
Put trypsase and cause the trypsase in blood to raise.Therefore, asparaginase is easier by trypsin degradation.For
The asparaginase that determination Nano particles of silicon dioxide disclosed herein prevents from being wherein encapsulated is by trypsin degradation
Protective effect, trypsase is carried out to free asparaginase or the asparaginase being encapsulated in Nano particles of silicon dioxide and disappeared
Change, and the residual activity of asparaginase is determined by asparaginase activity analysis.Therefore, trypsin resistance is carried out
Test to assess Nano particles of silicon dioxide to the protective effect for the asparaginase being wherein encapsulated.
By all free asparaginases containing 0.8U asparaginases and the asparaginase that is encapsulated in PEG-HSN from
The heart and it is scattered in 200 μ L Tris buffer solutions (0.05M, pH 8.6), with trypsase (1.5U/40 μ L, in NaH2PO4Buffering
In solution) mixing, and progress Trypsin Induced 2 hours at 37 DEG C.After digestion, surveyed by asparaginase activity analysis
Asparaginase activity in random sample product.
Trypsin resistance analysis is carried out to following group:Free asparaginase, repair through PEG- trimethoxy silanes
The asparaginase (" PEG- asparaginases ") of decorations is encapsulated in (" PEG- asparagines in the double-deck PEG-HSN of no TA modifications
Enzyme@PEG-HSN 15 "), through PEG- trimethoxy silanes modify asparaginase be encapsulated in TA modification double-deck PEG-
In HSN (" PEG- asparaginase@PEG-HSN 17 "), wherein 0.8U asparaginases are contained in all groups.Determine every group of phase
Compared with the relative asparaginase activity of control group (free asparaginase, without Trypsin Induced).As a result show,
PEG- asparaginase@PEG-HSN 15 and 17 can reach about 100% relative activity in 6 hours.By contrast, freely
Asparaginase after digestion, was only capable of reaching 10% relative asparaginase activity in 8 hours.In view of described above, capsule
The asparaginase being encapsulated in double-deck Nano particles of silicon dioxide is better than free asparagine to the tolerance of Trypsin Induced
Enzyme.As a result egg can be prevented to the protein/enzyme offer being wherein encapsulated by disclosing Nano particles of silicon dioxide disclosed herein
The excellent protective effect of white enzyme degraded.
Example 5
As known in art, the weary egg caused in tumour cell (such as acute leukemia cellses) of consumption of altheine
White matter synthesis is suppressed, and thus causes cell death.It is encapsulated in by following experiment to test in Nano particles of silicon dioxide
Asparaginase cytotoxicity:
Cell culture
MOLT-4 and Jie Kate cells (Jurkat cells) (are that acute human lymphoblastic leukemia suspends carefully
Born of the same parents be, obtained from living resources collect and research center (Taiwan)), (mouse mammary carcinoma cell line, this tumour are animal IV to 4T1
Phase human breast cancer;Give acquisition by another laboratory) and A549 (human lung carcinoma cell lines, given and obtained by another laboratory
) cultivated in the RPMI-1640 culture mediums in containing 10% hyclone (FBS), in collecting and study obtained from living resources
The BxPc-3 (human pancreas's cancerous cell line) of the heart (Taiwan) is containing 10mM HEPES, 1mM Sodium Pyruvates and 10% hyclone
(FBS) in RPMI-1640 culture mediums, in the 5%CO of humidification2Cultivated in atmosphere, at 37 DEG C, and all prior culture medias are equal
Contain 100U/mL penicillin and 100 μ g/mL streptomysins.When cell reaches about 60-70% converges when, harvest its be used for subculture training
Support.
Cytotoxicity analysis (are analyzed) using WST-1
In this experiment, with respectively containing 0.4,0.4,0.2 or 1U/mL asparaginases free asparaginase,
PEG- asparaginases PEG-HSN 15 and 17 handles Leukemia Cell Lines (MOLT-4 and Jie Kate), breast cancer cell line (4T1)
With Stem Cells system (BxPc-3).PEG-HSN 18 and 19 handles the (Hes of PEG- asparaginase@PEG-HSN 15 as a control group
17 control group, without asparaginase).Specifically, according to every hole 4 × 10 in 24 porose discs5Individual cell inoculation is acute white
Blood disease cell (MOLT-4 and Jie Kate) and according to every hole 2x104Individual cell is inoculated with 4T1 cell lines, and handles 24 with foregoing group
Or 72 hours.According to every hole 4x10 in 96 porose discs3Individual cell is inoculated with Stem Cells system (BxPc-3) and handled with foregoing group
48 hours.Then will be cultivated 30 minutes at 37 DEG C together with cell and WST-1 reagents (clone scientific & technical corporation (Clontech)), and
Brightness is inhaled to detect yellow formazan caused by living cells with micro- quantitative disc type reader (Bio-Red, model 680) measurement 450nm
Dyestuff.Cell without any processing is used as 100% cell survival rate tester.As shown in figure 4, PEG- asparaginases@
PEG-HSN 15 and 17 presents the excellent cell for MOLT-4 Leukemia Cell Lines similar to free asparaginase
Toxicity.As a result show, significant impact will not be produced to its bioactivity by being encapsulated asparaginase with Nano particles of silicon dioxide.Separately
Outside, because PEG-HSN 18 and 19 does not show obvious cytotoxicity, it is believed that PEG- asparaginase@PEG-HSN 15
Cytotoxicity with 17 is due merely to asparaginase.In addition to MOLT-4 Leukemia Cell Lines, we are also to outstanding card extra white
Blood disease cell line, 4T1 breast cancer cell lines and BxPc-3 pancreatic cancer cells system have carried out cytotoxicity analysis.As a result show, PEG-
Asparaginase@PEG-HSN 15 and 17 present the cytotoxicity for these JEG-3s.
Example 6
Cell absorption analysis
MOLT-4 and A549 cells are determined to two by FACS Calibur flow cytometries (BD Biosciences)
The cell absorption efficiency of silicon oxide nanoparticle.It is glimmering with glowing of being combined altogether of the asparaginase in Nano particles of silicon dioxide
Fluorescein dye (rhodamine-B- isothiocyanates;RITC the mark of the cell absorption efficiency of quantitative determination particle) is served as.MOLT-4
It is identical with described in example 5 with the cell culture condition of A549 cells.Specifically, the inoculation 1 × 10 per hole in 6 porose discs6It is individual
MOLT-4 cells or 2 × 105Individual A549 cells and with (the every milliliter of particle of PEG- asparaginase@PEG-HSN 15 and 17
0.9mg) cultivated 24 hours in the culture medium containing serum together.Then wash cell twice with PBS, harvest, centrifuge and enter
Row flow cytometry is to detect its fluorescence signal.Calculated according to the ratio of the cell with fluorescence signal and whole cells
Cell absorptivity;Average fluorescent strength (MFI) is the average value of the fluorescence intensity of the cell with fluorescence signal.Such as Fig. 5 (A) institute
Show, PEG- asparaginase@PEG-HSN 15 and 17 present good cell in MOLT-4 Leukemia Cell Lines and absorbed
Efficiency, and the cell of the Nano particles of silicon dioxide PEG- asparaginase@PEG-HSN 17 through the modification of TA- trimethoxy silanes
Absorption efficiency is higher.It is without being bound by theory, the caused PEG- asparaginase@PEG- with more positive charges are modified by TA
HSN 17 causes Nano particles of silicon dioxide to be easier to be absorbed by cell.As a result it is also shown that being carried out to Nano particles of silicon dioxide
Different modifying can be used for adjusting its characteristic, such as cell absorption efficiency.As shown in Fig. 5 (B), two groups of average fluorescent strength
(MFI) it is similar.In addition to MOLT-4 Leukemia Cell Lines, also demonstrate that PEG- asparaginase@PEG-HSN 15 and 17 can be by
A549 lung cancer cell lines (solid tumor cell system) absorb.
Example 7
Apoptosis assay
In order to study influence of the asparagine enzyme therapy to Apoptosis degree, 1 × 10 is inoculated with 6 porose discs6Individual MOLT-
4 cells (MOLT-4 cell culture condition is identical with described in example 2) and in the culture medium containing serum, at 37 DEG C use from
By asparaginase, PEG- asparaginase@PEG-HSN 15 and 17 and PEG-HSN containing 0.4U/mL asparaginases
18 and 19 (PEG- asparaginase@PEG-HSN 15 and 17 control groups, be not encapsulated asparaginase) are handled 24 hours.By from
The heart (400g, 10 minutes, 4 DEG C) harvesting, is washed with PBS, with 4'6- diformazans amidino groups -2-phenylindone dihydrochloride (DAPI;
1 μ g/mL) dye 10 minutes, washed again with PBS, and in the 1mL PBS being resuspended in 6 porose discs.In inversion type fluorescence microscopy
The nuclear morphology change and cell that cell is observed under mirror (Olympus (Olympus), magnifying power 40X, mercury lamp excite for UV) are withered
Die main body (produced by DNA fragmentation).As shown in fig. 6, with free asparaginase (d)) and PEG- asparaginase@PEG-
HSN 15 and 17 (e) and f)) the MOLT-4 cells of processing present Apoptosis sign.As a result show, be encapsulated in middle this paper institutes
Asparaginase in disclosed Nano particles of silicon dioxide presents the inducing cell apoptosis similar to free asparaginase
The effect of.
Example 8
Nano particles of silicon dioxide is from the removing in the circulatory system
It is studied from mouse using PEG- asparaginase@PEG-HSN (there is the RITC combined altogether with asparaginase)
The speed removed in the circulatory system.Specifically, by PEG- asparaginase@PEG-HSN 15 and 17 (in PBS, 30mg/mL
Dosage) it is injected intravenously into the BALB/c nude mouses with 4T1 tumours (8 week old).Mouse is observed under Two Photon Fluorescence
Blood vessel in ear, and 10,30,60 and 120 minutes after injection obtain real-time imaging.As shown in Figure 7, PEG- asparagus ferns acyl
Amine enzyme@PEG-HSN 15 signal attenuation is very slowly (or even still can detect signal after 120 minutes after injection)
(Fig. 7, up);By contrast, PEG- asparaginases@PEG-HSN 17 fluorescence signal is in identical time point then much weaker
(Fig. 7, descending).Circulation time is longer, shows that half-life period in blood is longer.As a result show, the PEG- with more positive charges
Asparaginase@PEG-HSN 17 (having the modification of TA- trimethoxy silanes) are easier to be eliminated from blood.It may infer that
Go out, the half-life period of modification (such as TA modifications) regulation Nano particles of silicon dioxide in blood can be utilized.In addition, although in blood
In circulation time it is different, but PEG- asparaginase@PEG-HSN 15 and 17 fine dispersion and are not formed bright in blood
Aobvious aggregation, this shows that Nano particles of silicon dioxide has good live body internal stability.
Example 9
Bio distribution is analyzed
PEG- asparaginase@PEG-HSN 15 and 17 are injected intravenously into (in PBS, 30mg/mL dosage) to be had
In the BALB/c nude mouses (9 week old) of tumour.Nano particles of silicon dioxide is observed under IVIS fluoroscopic imaging systems (Lumina)
Bio distribution in major organs (including heart, lung, spleen, liver and kidney), tumour, urine and blood.As shown in figure 8,
After injection 24 hours, PEG- asparaginase@PEG-HSN 15 (up) and 17 (descending) are main be stranded in respectively tumour with
In liver and liver;Two kinds of nano-particles can be found in kidney;Do not observed in urine and blood significant
Signal.As a result show, PEG- asparaginase@PEG-HSN 15 can more easily be stranded in tumor tissues and provide by
Bioactive ingredients are delivered to the effective means of tumour;As a result it is also shown that PEG- asparaginase@PEG-HSN 15 make nanoparticle
Son shows excellent reinforcing permeability and is detained (EPR) effect, so that it is accumulated in tumour.Believe PEG- asparagines
Accumulation of the enzyme@PEG-HSN 17 in tumour is caused by it is quickly removed from the circulatory system less.As a result show, can utilize
Modify the bio distribution feature of (such as TA modifications) regulation Nano particles of silicon dioxide.
Those skilled in the art in the invention to teachings of the present invention and disclosure it should be appreciated that can change
And retouching, and these changes and retouching do not depart from the spirit and scope of the present invention.According to the above, the application wishes to cover it
Any change and retouching, condition are that the change or retouching belong to such as appended claims or its equivalent limited range
It is interior.
Claims (29)
1. a kind of Nano particles of silicon dioxide, comprising
Multi-layer silica dioxide housing, wherein each housing has mesoporous gap and surrounds the hollow space of closing, it is described inner most
Closed hollow space optionally has silica solid core;And
One or more are encapsulated in the bioactive ingredients in the space, are encapsulated wherein the size of the bioactive ingredients is more than
The pore-size of its housing, and the bioactive ingredients in wherein each space can be identical or different.
2. Nano particles of silicon dioxide according to claim 1, it has about 20nm to the granularity about in the range of 500nm.
3. Nano particles of silicon dioxide according to claim 1, it has about 20nm to the granularity about in the range of 150nm.
4. Nano particles of silicon dioxide according to claim 1, it has two or more housings.
5. Nano particles of silicon dioxide according to claim 1, wherein each housing has organic silica residue.
6. Nano particles of silicon dioxide according to claim 1, wherein the pore-size of the housing is less than 5nm.
7. Nano particles of silicon dioxide according to claim 1, wherein the housing has about 2nm to about independently of one another
15nm thickness.
8. Nano particles of silicon dioxide according to claim 1, wherein the size in the space is adjustable.
9. Nano particles of silicon dioxide according to claim 1, wherein the size in the space between the housing is
In the range of 2nm to 75nm.
10. Nano particles of silicon dioxide according to claim 1, wherein the bioactive ingredients itself or there is surface
The bioactive ingredients of modification can be dispersed or dissolved in aqueous phase.
11. Nano particles of silicon dioxide according to claim 1, wherein the bioactive ingredients are enzyme, protein medicine
Thing, antibody, vaccine, antibiotic or nucleotides medicine.
12. Nano particles of silicon dioxide according to claim 11, wherein the enzyme be Ah add'sing carbohydrase, Imiglucerase, he
Sharp glycosides enzyme, Wella glycosides enzyme, alglucerase, Sai Beili enzymes, La Luoni enzymes, Chinese mugwort Du's sulphur enzyme, angstrom Lip river sulphur enzyme plus sulphur enzyme, Ah's glucoside
Enzyme, asparaginase, glutaminase, arginine deiminase, arginase, methioninase, cysteine enzyme, high half Guang
Propylhomoserin enzyme, PAH, Phenylalanine ammonia lyase, urate oxidase, catalyzing enzyme, HRPO, super oxygen
Mutase or glutathione peroxidase.
13. Nano particles of silicon dioxide according to claim 1, wherein PEG (PEG) or cancer target coordination
Body is optionally coupled to the outer surface of each housing.
14. a kind of method for preparing Nano particles of silicon dioxide, comprise the steps of:
(a) any one of step (a-1) and (a-2):
(a-1) oil phase, surfactant, alkoxy silane and/or silicate source, wherein optional containing one or more lifes is provided
The aqueous phase of thing active component and optional cosurfactant, to form Water-In-Oil (W/O) type microemulsion;With
(a-2) oil phase, surfactant, alkoxy silane and/or silicate source and optional cosurfactant are provided, with
Form mixture;
(b) into the W/O microemulsions of (a-1), addition triggers reagent, or the water-based initiation examination of mixture addition to (a-2)
Agent, to form Water-In-Oil (W/O) type microemulsion, be subsequently formed silica nanometer core, the silica nanometer core and its table
Bioactive ingredients on face are bonded and/or are encapsulated in the bioactive ingredients wherein;
(c) aqueous phase containing bioactive ingredients is provided;
(d) alkoxy silane and/or silicate source are introduced, to form the another of the silica nanometer core of encirclement (b)
Individual silicon dioxide layer;
(e) step (c) and (d) are optionally repeated one or more times;
(f) stabilization removal condition is implemented so that the W/O microemulsions stabilization removal and collection is thusly-formed by the microemulsion
Gained particle;And
(g) particle collected in step (f) is scattered in Aqueous wash phase, to obtain the silica dioxide nano particle
Son;
The alkoxy silane and/or silicate source wherein in step (d) and (e) and optionally described in step (a)
Alkoxy silane and/or silicate source include at least one organoalkoxysilane, and
The size of wherein described bioactive ingredients is more than the pore-size for being encapsulated its Silica Shell.
15. according to the method for claim 14, will be wherein optional living containing one or more biologies wherein in step (a-1)
Property composition the aqueous phase and the order that introduces of the alkoxy silane and/or silicate source be tradable or simultaneously.
16. according to the method for claim 14, wherein the oil phase be dodecane, decane, octane, hexane, hexamethylene,
Benzene,toluene,xylene triglyceride oil or vegetable oil.
17. according to the method for claim 14, wherein the surfactant is nonionic surface active agent.
18. according to the method for claim 17, wherein the nonionic surface active agent is poly- (ethylene oxide) nonyl
Phenyl ether, polyoxyethylene glycol sorbitan alkyl esters, polyethylene glycol alkyl ether, glucoside alkyl ether, polyethylene glycol are pungent
Base phenyl ether, polyalkylene glycol alkyl phenyl ether, alkyl esters of glycerol, polypropylene glycol alkyl ether, poloxamer, coconut oleoyl amine MEA, coconut palm
Oleamide DEA, lauryl dimethyl amine oxide or polyethoxylated tallow amine.
19. according to the method for claim 14, wherein the alkoxy silane and/or silicate source are phase independently of one another
It is same or different.
20. according to the method for claim 14, wherein the alkoxy silane and/or silicate source include tetraethoxy-silicane
Alkane (TEOS), tetramethoxy-silicane (TMOS), sodium metasilicate or its mixture.
21. according to the method for claim 14, wherein the organoalkoxysilane is 2- [methoxyl groups (polyethyleneoxy)
Propyl group]-trimethoxy silane (PEG- trimethoxy silanes), 3- TSL 8330s (APTMS), the ethoxy of propyl group three
Base silane, butyl trimethoxy silane, octyl group trimethoxy silane, diphenyl diethoxy silane, n-octyl triethoxysilicane
Alkane, mercaptopropyi trimethoxy silane, chloromethyl trimethoxy silane, isobutyl triethoxy silane, the second of 3- aminopropyls three
TMOS, ethyl trimethoxy styrene silane, MTES, phenyl triethoxysilane (PTEOS), phenyl
Trimethoxy silane (PTMOS), MTMS (MTMOS), ethyltriacetoxysilane (ETAS), N- (front threes
TMOS base propyl group) ethylenediamine triacetic acid (EDTAS), (3- ortho-siliformic acids base) propylmethylposphonate (THPMP), methyl
Triacetoxysilane (MTAS), N- [3- (trimethoxy silane base) propyl group] ethylenediamine, trimethoxysilylpropyl modification
Polyethyleneimine, (3- mercaptopropyis) trimethoxy silane (MPTMS), N- [3- (trimethoxy silane base) propyl group]-N, N,
N- trimethyl ammonium chlorides, amphoteric ion type silane or its mixture.
22. according to the method for claim 14, wherein the alkoxy silane and/or silicate source are TEOS and APTMS
Mixture, THPMP, APTMS and TEOS mixture, or EDTAS, APTMS and TEOS mixture.
23. according to the method for claim 14, wherein when using step (e), wherein the Nano particles of silicon dioxide
The number of the housing be by make decision:The alkoxy silane and/or silicate source, wash time and carry out described in
The temperature of washing.
24. according to the method for claim 14, wherein the aqueous phase is water, aqueous buffer solution, the DMSO aqueous solution or alkanol
The aqueous solution or the solution containing cosolvent.
25. the method according to claim 11, wherein step (a), (c) and the bioactive ingredients in (e) are each
It is independently identical or different.
26. according to the method for claim 14, wherein the bioactive ingredients itself or described with surface modification
Bioactive ingredients can be dispersed or dissolved in aqueous phase.
27. according to the method for claim 14, wherein the bioactive ingredients are enzyme, pharmaceutical grade protein, antibody, epidemic disease
Seedling, antibiotic or nucleotides medicine.
28. according to the method for claim 27, wherein the enzyme is Ah add'sing carbohydrase, Imiglucerase, his sharp glycosides enzyme, Wella glycosides
Enzyme, alglucerase, Sai Beili enzymes, La Luoni enzymes, Chinese mugwort Du sulphur enzyme, angstrom Lip river sulphur enzyme plus sulphur enzyme, Ah's glucosidase, asparaginase,
Glutaminase, arginine deiminase, arginase, methioninase, cysteine enzyme, Homocysteine desulfurase, phenylpropyl alcohol ammonia
Sour hydroxylase, Phenylalanine ammonia lyase, urate oxidase, catalyzing enzyme, HRPO, superoxide dismutase or gluathione
Peptide peroxidase.
29. a kind of Nano particles of silicon dioxide, prepared by its method according to any claim in claim 14 to 28.
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CN110108656A (en) * | 2019-05-31 | 2019-08-09 | 吉林大学 | A kind of method of the fixed uricase detection uric acid of mesoporous organosilicon hollow nanospheres |
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